Abstract The long term goal is to understand the how physiologically relevant environments influence protein-protein interactions both in vitro and in living cells. Quinary structure occurs solely in the crowded cellular environment and involves nonspecific interactions between a protein and the macromolecules that surround it. These interactions by definition are absent in dilute buffered solutions. Protein-protein interactions are generally understood as protein complexes comprise >50% of the RCSB Protein Data Bank structures. Nearly all of these structures were studied in dilute buffered solutions where the macromolecule concentration is negligible. In a proteins native environment, the cell, the macromolecule concentration is >300 g/L, giving rise to quinary interactions. Our knowledge of how quinary interactions influence protein-protein interactions is lacking. Thus is it imperative to understand how the cellular environment effects protein-protein interactions. To do so we use the simplest model, a homodimer to investigate the influence of quinary interactions on protein-protein interactions using three specific aims. Aim 1: Determine how hard-core repulsions influence protein-protein interactions using 19F NMR and scaled particle theory Aim 2: Determine how chemical interactions influence protein-protein interactions by using protein cosolutes, lysates, and by modulating the electrostatic environment. Aim 3: Determine how the cellular environment effects protein-protein interactions using in-cell NMR and the domain swapped dimer. At the conclusion of these studies we will understand how the complex cellular environment effects protein- protein interactions. This knowledge will provide fundamental knowledge for understanding the forces that influence protein complexes in cells and how their disruption can lead to disease.